Calpain activation mediates microgravity-induced myocardial abnormalities in mice via p38 and ERK1/2 MAPK pathways

Abstract

The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities. The human cardiovascular system has adapted to function optimally in Earth's 1G gravity, and microgravity conditions cause myocardial abnormalities, including atrophy and dysfunction. However, the underlying mechanisms linking microgravity and cardiac anomalies are incompletely understood. In this study, we investigated whether and how calpain activation promotes myocardial abnormalities under simulated microgravity conditions. Simulated microgravity was induced by tail suspension in mice with cardiomyocyte-specific deletion of Capns1, which disrupts activity and stability of calpain-1 and calpain-2, and their WT littermates. Tail suspension time-dependently reduced cardiomyocyte size, heart weight, and myocardial function in WT mice, and these changes were accompanied by calpain activation, NADPH oxidase activation, and oxidative stress in heart tissues. The effects of tail suspension were attenuated by deletion of Capns1. Notably, the protective effects of Capns1 deletion were associated with the prevention of phosphorylation of Ser-345 on p47phox and attenuation of ERK1/2 and p38 activation in hearts of tail-suspended mice. Using a rotary cell culture system, we simulated microgravity in cultured neonatal mouse cardiomyocytes and observed decreased total protein/DNA ratio and induced calpain activation, phosphorylation of Ser-345 on p47phox, and activation of ERK1/2 and p38, all of which were prevented by calpain inhibitor-III. Furthermore, inhibition of ERK1/2 or p38 attenuated phosphorylation of Ser-345 on p47phox in cardiomyocytes under simulated microgravity. This study demonstrates for the first time that calpain promotes NADPH oxidase activation and myocardial abnormalities under microgravity by facilitating p47phox phosphorylation via ERK1/2 and p38 pathways. Thus, calpain inhibition may be an effective therapeutic approach to reduce microgravity-induced myocardial abnormalities. Spaceflight or microgravity conditions are associated with myocardial atrophy, which contributes to the functional depression of the heart (1Scott J.M. Warburton D.E.R. Williams D. Whelan S. Krassioukov A. Challenges, concerns and common problems: physiological consequences of spinal cord injury and microgravity.Spinal Cord. 2011; 49 (20498665): 4-1610.1038/sc.2010.53Crossref PubMed Scopus (28) Google Scholar, 2Yoshida T. Tabony A.M. Galvez S. Mitch W.E. Higashi Y. Sukhanov S. Delafontaine P. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.Int. J. Biochem. Cell Biol. 2013; 45 (23769949): 2322-233210.1016/j.biocel.2013.05.035Crossref PubMed Scopus (78) Google Scholar, 3Summers R.L. Martin D.S. Meck J.V. Coleman T.G. Computer systems analysis of spaceflight induced changes in left ventricular mass.Comput. Biol. Med. 2007; 37 (16808910): 358-36310.1016/j.compbiomed.2006.04.003Crossref PubMed Scopus (23) Google Scholar). Depressed myocardial function is an important factor leading to post-flight orthostatic intolerance (4Convertino V.A. Status of cardiovascular issues related to space flight: implications for future research directions.Respir. Physiol. Neurobiol. 2009; 169 (19383556): S34-S3710.1016/j.resp.2009.04.010Crossref PubMed Scopus (41) Google Scholar, 5Goswami N. Roma P.G. De Boever P. Clément G. Hargens A.R. Loeppky J.A. Evans J.M. Peter Stein T. Blaber A.P. Van Loon J.J.W.A. Mano T. Iwase S. Reitz G. Hinghofer-Szalkay H.G. Using the Moon as a high-fidelity analogue environment to study biological and behavioral effects of long-duration space exploration.Planet. Space Sci. 2012; 74: 111-12010.1016/j.pss.2012.07.030Crossref Scopus (17) Google Scholar). However, the exact mechanisms that govern the regulation of myocardial atrophy in microgravity are incompletely understood. Protein degradation systems play important roles in muscle atrophy (6Sandri M. Protein breakdown in muscle wasting: role of autophagy-lysosome and ubiquitin-proteasome.Int. J. Biochem. Cell Biol. 2013; 45 (23665154): 2121-212910.1016/j.biocel.2013.04.023Crossref PubMed Scopus (336) Google Scholar). There are three major protein degradation systems in the cardiovascular system, including the calpain system, autophagy, and the ubiquitin proteasome system (7Nishida K. Yamaguchi O. Otsu K. Degradation systems in heart failure.J. Mol. Cell. Cardiol. 2015; 84 (25981331): 212-22210.1016/j.yjmcc.2015.05.004Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Previous studies investigated the muscle RING finger protein-1 (MuRF1), an E3 ubiquitin ligase, and atrogin-1, a striated muscle-specific ubiquitin ligase, in the development of cardiac muscle atrophy under certain conditions (8Willis M.S. Parry T.L. Brown D.I. Mota R.I. Huang W. Beak J.Y. Sola M. Zhou C. Hicks S.T. Caughey M.C. D'Agostino Jr., R.B. Jordan J. Hundley W.G. Jensen B.C. Doxorubicin exposure causes subacute cardiac atrophy dependent on the striated muscle-specific ubiquitin ligase MuRF1.Circ. Heart Fail. 2019; 12 (30871347)e005234 10.1161/circheartfailure.118.005234Crossref PubMed Scopus (27) Google Scholar, 9Maejima Y. Usui S. Zhai P. Takamura M. Kaneko S. Zablocki D. Yokota M. Isobe M. Sadoshima J. Muscle-specific RING finger 1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A.Circ. Heart Fail. 2014; 7 (24526353): 479-49010.1161/CIRCHEARTFAILURE.113.000713Crossref PubMed Scopus (29) Google Scholar, 10Willis M.S. Rojas M. Li L. Selzman C.H. Tang R.H. Stansfield W.E. Rodriguez J.E. Glass D.J. Patterson C. Muscle ring finger 1 mediates cardiac atrophy in vivo.Am. J. Physiol. Heart Circ. Physiol. 2009; 296 (19168726): H997-H100610.1152/ajpheart.00660.2008Crossref PubMed Scopus (77) Google Scholar). It was reported that autophagy is induced during regression of cardiac hypertrophy by unloading of the heart (11Oyabu J. Yamaguchi O. Hikoso S. Takeda T. Oka T. Murakawa T. Yasui H. Ueda H. Nakayama H. Taneike M. Omiya S. Shah A.M. Nishida K. Otsu K. Autophagy-mediated degradation is necessary for regression of cardiac hypertrophy during ventricular unloading.Biochem. Biophys. 2013; PubMed Scopus Google Scholar, N. Y. C. Usui S. S. Y. Sadoshima J. an role in regression of hypertrophy during unloading of the 2013; PubMed Scopus Google and in myocardial atrophy induced by tail suspension H. Y. Li of autophagy cardiac and atrophy in to Sci. 2015; PubMed Scopus Google a microgravity. inhibition of autophagy reduced myocardial atrophy and in tail-suspended H. Y. Li of autophagy cardiac and atrophy in to Sci. 2015; PubMed Scopus Google an important role of autophagy in myocardial However, is on the role of calpain in myocardial atrophy under microgravity. to a of with major of calpain-1 and calpain-2, are of by and and a common by Capns1. The is for calpain-1 and and of Capns1 disrupts calpain-1 and Li H. W. J. The calpain PubMed Scopus Google Scholar). in cardiac injury to a of and the of heart C. H. D. D.J. S. T. deletion of cell calpain in mice by 2019; PubMed Scopus Google Scholar, J. Y. J. of the activity and in hearts J. Physiol. Cell Physiol. 2019; Scopus Google Scholar, T. S. D. G. Y. T. calpain-1 in heart in role of Cardiol. 2019; PubMed Scopus (27) Google Scholar, T.L. S. L. Y. G. A. D. of the in cardiac is during Mol. Cell Cardiol. 2019; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Huang A. J. C. W. R.L. J. calpain for heart implications Sci. PubMed Scopus Google Scholar, D. S. D.J. T. R.B. Y. T. calpain-1 disrupts and in 1 a to Google Scholar, D. Y. T. W. R.B. T. of the heart injury by and Heart Fail. 2015; PubMed Scopus Google Scholar, J. M. Li J. H. W. M. T. of protein and myocardial Biol. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. H. M. D. J.M. T. inhibition of calpain myocardial hypertrophy and in mouse of 1 2011; PubMed Scopus Google Scholar). study that unloading of the heart the calpain system and induced myocardial atrophy P. S. H. unloading of the heart the calpain Mol. Cell. Cardiol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). calpain activation was observed in hearts of with tail suspension H. L. Li Y. of regulates in cardiomyocytes of tail-suspended Cell. Biochem. 2011; PubMed Scopus Google Scholar). studies a role of calpain in microgravity-induced myocardial NADPH contributes to muscle atrophy under conditions T. Tabony A.M. Galvez S. Mitch W.E. Higashi Y. Sukhanov S. Delafontaine P. Molecular mechanisms and signaling pathways of angiotensin II-induced muscle wasting: potential therapeutic targets for cardiac cachexia.Int. J. Biochem. Cell Biol. 2013; 45 (23769949): 2322-233210.1016/j.biocel.2013.05.035Crossref PubMed Scopus (78) Google Scholar, Protein in on 12 PubMed Scopus Google Scholar). In NADPH oxidase and are of NADPH oxidase K. The of NADPH and 2007; PubMed Scopus Google Scholar, A. M. Shah A.M. NADPH and cardiac Fail. 2011; PubMed Scopus Google Scholar). The NADPH oxidase is of a or and and a p47phox, and a of NADPH oxidase including phosphorylation of their to the and the of and K. The of NADPH and 2007; PubMed Scopus Google Scholar, L. H. M. J. NADPH oxidase activation in role of the phosphorylation of J. PubMed Scopus Google Scholar). p47phox has phosphorylation which Ser-345 is in a protein that is by p38 and ERK1/2 of the L. H. M. J. NADPH oxidase activation in role of the phosphorylation of J. PubMed Scopus Google Scholar). of Ser-345 on p47phox causes changes of p47phox by the facilitating phosphorylation on leading to activation of the NADPH oxidase L. H. M. J. NADPH oxidase activation in role of the phosphorylation of J. PubMed Scopus Google Scholar). reported that inhibition of NADPH oxidase cardiomyocyte and heart and myocardial function in tail-suspended mice L. W. L. Li H. L. T. of cardiomyocyte and myocardial in tail-suspended mice by p47phox NADPH oxidase activation and Med. 2019; PubMed Scopus Google an important role of NADPH oxidase in microgravity-induced myocardial abnormalities. However, how NADPH oxidase activation is in to and has whether calpain regulates NADPH oxidase activation under microgravity. In this study, we investigated whether and how calpain promotes NADPH oxidase activation and oxidative leading to myocardial abnormalities during simulated microgravity. Tail suspension for and in muscle unloading Tail suspension for in of calpain in WT mouse heart the of calpain were in mouse hearts of tail suspension calpain were in mouse hearts and of tail suspension calpain activation in tail-suspended mouse This activation of calpain negatively with heart and myocardial function and and cardiomyocyte in tail-suspended mice. Tail suspension for reduced the of 1 in WT mouse hearts and tail deletion of Capns1 in heart cardiomyocyte and myocardial function in Capns1 mice with their WT and deletion of Capns1 has to the stability and of calpain-1 and in the heart Y. J. H. M. D. J.M. T. inhibition of calpain myocardial hypertrophy and in mouse of 1 2011; PubMed Scopus Google these that inhibition of calpain myocardial abnormalities under microgravity. However, cardiomyocyte-specific of calpain muscle in tail-suspended mice study reported that simulated microgravity induced NADPH oxidase activation in tail-suspended mouse hearts L. W. L. Li H. L. T. of cardiomyocyte and myocardial in tail-suspended mice by p47phox NADPH oxidase activation and Med. 2019; PubMed Scopus Google Scholar). in tail suspension for in protein of of NADPH including p47phox, and in cell of NADPH oxidase activation, as activation of NADPH oxidase the of to the L. H. M. J. NADPH oxidase activation in role of the phosphorylation of J. PubMed Scopus Google and their in cell tail their in heart were The activation of NADPH oxidase with calpain activation in tail-suspended mouse hearts in a Notably, of Capns1 reduced the protein of p47phox, and in the cell of tail-suspended mouse that of calpain-1 and NADPH oxidase activation in tail-suspended mouse hearts In with activation of NADPH was observed in heart of tail-suspended mice with as was protein and of protein and and However, was in tail-suspended mice with their WT of Capns1 in oxidative in hearts of tail-suspended mice as by protein and and cardiomyocytes and we as is through mechanisms S. Zhai P. D. Zablocki D. N. M. Sadoshima J. of NADPH oxidase in the promotes cardiomyocyte autophagy and during stress through the protein factor factor 2013; PubMed Scopus Google Scholar). Tail suspension in protein of in tail-suspended mouse hearts However, of Capns1 the protein of to tail suspension In tail suspension deletion of Capns1 and oxidase activity in tail-suspended mouse hearts and oxidative may a of we the in in tail suspension deletion of Capns1 the of and in heart tissues. the that changes of play a role in calpain oxidative stress in tail-suspended mouse the potential mechanisms by which calpain NADPH oxidase activation, we on the phosphorylation of p47phox as a for of this of NADPH oxidase to the cell L. H. M. J. NADPH oxidase activation in role of the phosphorylation of J. PubMed Scopus Google Scholar). to the of NADPH oxidase to the the of phosphorylation of Ser-345 on p47phox were in mouse hearts and tail suspension in tail-suspended mice, deletion of Capns1 in of phosphorylation of Ser-345 on p47phox that calpain promotes phosphorylation of Ser-345 on p47phox in NADPH oxidase activation in tail-suspended mouse the role of calpain in p47phox we simulated microgravity in cultured cardiomyocytes the rotary cell culture Simulated microgravity calpain and this was with a of total protein/DNA ratio and an in phosphorylation of Ser-345 on p47phox with calpain prevented calpain activation, total protein/DNA and attenuated microgravity-induced phosphorylation of Ser-345 on p47phox in cardiomyocytes the of calpain on p47phox phosphorylation in tail-suspended mouse phosphorylation of Ser-345 on p47phox is by ERK1/2 and p38 L. H. M. J. NADPH oxidase activation in role of the phosphorylation of J. PubMed Scopus Google we the phosphorylation of ERK1/2 and p38 in tail-suspended mouse in the of ERK1/2 and p38 were in WT mouse hearts tail suspension of the and tail suspension were of the Thus, we ERK1/2 and p38 in mice and their WT tail in and the of ERK1/2 and p38 were in mice with their WT tail that calpain may phosphorylation of ERK1/2 and p38 in the first in tail-suspended mouse this in cultured we that the protein of ERK1/2 were simulated microgravity with calpain prevented ERK1/2 phosphorylation in cardiomyocytes simulated microgravity The protein of p38 were and simulated microgravity to the of calpain inhibition on p38 phosphorylation simulated microgravity. with calpain prevented p38 phosphorylation of ERK1/2 or p38 activation with or attenuated phosphorylation of Ser-345 on p47phox in cultured cardiomyocytes of simulated microgravity and the analysis for ERK1/2 and p38 phosphorylation that ERK1/2 phosphorylation the p38 phosphorylation was the in cardiomyocytes simulated microgravity we whether ERK1/2 p38 phosphorylation induced by microgravity. However, inhibition of ERK1/2 with the of p38 in cardiomyocytes simulated microgravity that ERK1/2 and p38 p47phox phosphorylation in ERK1/2 and p38 their roles and of In of this of and p47phox phosphorylation in microgravity with or these that calpain activation mediates microgravity-induced phosphorylation of Ser-345 on p47phox through p38 and ERK1/2 signaling in (8Willis M.S. Parry T.L. Brown D.I. Mota R.I. Huang W. Beak J.Y. Sola M. Zhou C. Hicks S.T. Caughey M.C. D'Agostino Jr., R.B. Jordan J. Hundley W.G. Jensen B.C. Doxorubicin exposure causes subacute cardiac atrophy dependent on the striated muscle-specific ubiquitin ligase MuRF1.Circ. Heart Fail. 2019; 12 (30871347)e005234 10.1161/circheartfailure.118.005234Crossref PubMed Scopus (27) Google Scholar, 9Maejima Y. Usui S. Zhai P. Takamura M. Kaneko S. Zablocki D. Yokota M. Isobe M. Sadoshima J. Muscle-specific RING finger 1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A.Circ. Heart Fail. 2014; 7 (24526353): 479-49010.1161/CIRCHEARTFAILURE.113.000713Crossref PubMed Scopus (29) Google Scholar, 10Willis M.S. Rojas M. Li L. Selzman C.H. Tang R.H. Stansfield W.E. Rodriguez J.E. Glass D.J. Patterson C. Muscle ring finger 1 mediates cardiac atrophy in vivo.Am. J. Physiol. Heart Circ. Physiol. 2009; 296 (19168726): H997-H100610.1152/ajpheart.00660.2008Crossref PubMed Scopus (77) Google and M.S. P. N. H. Glass D.J. Patterson C. cardiac hypertrophy in mice via of 2007; PubMed Scopus Google Scholar, C. H. Patterson C. atrophy cardiac hypertrophy by in an ubiquitin ligase PubMed Scopus Google in cardiac muscle atrophy or cardiac we the protein of and in Simulated microgravity in of and in cultured inhibition of calpain the protein of and in cardiomyocytes under conditions or microgravity The major of this study are that of calpain cardiomyocyte size, heart and myocardial function in tail-suspended mice, an important role of calpain in myocardial atrophy under microgravity. Furthermore, calpain activation mediates NADPH oxidase activation by facilitating p38 and ERK1/2 activation and phosphorylation of Ser-345 on p47phox in cardiomyocytes in to microgravity. Thus, this study an role of calpain in NADPH oxidase activation via p38 and ERK1/2 signaling during microgravity. activation was reported in heart tail-suspended H. L. Li Y. of regulates in cardiomyocytes of tail-suspended Cell. Biochem. 2011; PubMed Scopus Google and unloading mouse and human hearts P. S. H. unloading of the heart the calpain Mol. Cell. Cardiol. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). In with these this study demonstrates that tail suspension calpain activation in mouse deletion of Capns1 cardiomyocyte and heart and myocardial function in tail-suspended mice, a role of calpain in microgravity-induced myocardial atrophy and dysfunction. in study cultured cardiomyocytes the role of calpain in myocardial atrophy, as inhibition of calpain prevented the of protein/DNA ratio simulated microgravity. a study reported that of to reduce myocardial atrophy in a mouse of heart P. S. H. unloading of the heart the calpain Mol. Cell. Cardiol. 2007; Full Text Full Text PDF PubMed Scopus Google the heart of left ventricular a the heart of a tail-suspended in of inhibition of calpain by of muscle during muscle of a muscle and changes in during muscle Physiol. PubMed Scopus Google Scholar). is a in a spaceflight H. L. Li Y. of regulates in cardiomyocytes of tail-suspended Cell. Biochem. 2011; PubMed Scopus Google Scholar). reported that with the calpain activation and in cardiomyocytes Y. M. T. cardiomyocyte by NADPH calpain Biol. Med. 2009; PubMed Scopus Google Scholar). with a study that calpain activation was induced and to myocardial in during the tail suspension H. L. Li Y. of regulates in cardiomyocytes of tail-suspended Cell. Biochem. 2011; PubMed Scopus Google Scholar). Thus, calpain may a for prevention and for myocardial during and microgravity. study that NADPH oxidase is and oxidative stress is induced in tail-suspended mouse hearts and that inhibition of NADPH oxidase with cardiomyocyte and heart and myocardial function in tail-suspended mice L. W. L. Li H. L. T. of cardiomyocyte and myocardial in tail-suspended mice by p47phox NADPH oxidase activation and Med. 2019; PubMed Scopus Google Scholar). This an important role of NADPH oxidase in myocardial abnormalities under microgravity. activation of NADPH oxidase has in a of cardiac A. and of NADPH in the cardiovascular 2012; PubMed Scopus Google and of NADPH oxidase activation has the mechanisms underlying NADPH oxidase activation understood. important of this study is that calpain activation promotes NADPH oxidase activation in tail-suspended mouse This was by the of including p47phox, and to the cell and oxidative study that calpain activation promotes phosphorylation of Ser-345 on p47phox in tail-suspended mouse ERK1/2 and p38 in phosphorylation of Ser-345 on p47phox L. H. M. J. NADPH oxidase activation in role of the phosphorylation of J. PubMed Scopus Google Scholar). In with we that the protein of ERK1/2 and p38 are in cultured cardiomyocytes under microgravity and in tail-suspended mouse deletion of Capns1 or inhibition of calpain prevented the in ERK1/2 and p38 in tail-suspended mouse hearts or cultured cardiomyocytes under Furthermore, inhibition of ERK1/2 and p38 attenuated phosphorylation of Ser-345 on p47phox in cultured cardiomyocytes under microgravity. Thus, we that deletion of calpain phosphorylation of Ser-345 on p47phox by ERK1/2 and p38 activation, of of NADPH oxidase to the NADPH oxidase activation, and oxidative stress in tail-suspended mouse future studies are to how calpain mediates ERK1/2 and p38 activation during microgravity. It is important to that simulated microgravity ERK1/2 and p38 activation tail that ERK1/2 and p38 activation for NADPH oxidase the of microgravity. This is by in studies cultured inhibition of ERK1/2 or p38 attenuated p47phox phosphorylation in cardiomyocytes induced by simulated microgravity. It is that mechanisms NADPH oxidase activation and cardiomyocyte atrophy during the of which role of calpain in in cultured cardiomyocytes and mouse hearts under microgravity. In to NADPH oxidase and of are in including and oxidase D. M. role in cardiovascular and PubMed Scopus Google Scholar, S. C. J. by in to is by J. Cell Mol. Biol. PubMed Scopus Google Scholar, Moon Y. by NADPH and system and Biol. Med. PubMed Scopus Google Scholar). However, deletion of Capns1 and oxidase activity during microgravity in tail-suspended mouse It is important to that and oxidative stress is the of an and mechanisms P. M. oxidative and in under 2012; Google Scholar, and of J. Med. Biol. PubMed Scopus Google Scholar). the including and this study that deletion of Capns1 on the of these the that of the to oxidative stress in tail-suspended mouse In to autophagy and the ubiquitin proteasome system in protein degradation in the cardiovascular system (7Nishida K. Yamaguchi O. Otsu K. Degradation systems in heart failure.J. Mol. Cell. Cardiol. 2015; 84 (25981331): 212-22210.1016/j.yjmcc.2015.05.004Abstract Full Text Full Text PDF PubMed Scopus (23) Google which contributes to muscle the ubiquitin proteasome system has reported to cardiac muscle and are in cardiac muscle atrophy or cardiac muscle and inhibition of cardiac muscle atrophy under certain conditions (8Willis M.S. Parry T.L. Brown D.I. Mota R.I. Huang W. Beak J.Y. Sola M. Zhou C. Hicks S.T. Caughey M.C. D'Agostino Jr., R.B. Jordan J. Hundley W.G. Jensen B.C. Doxorubicin exposure causes subacute cardiac atrophy dependent on the striated muscle-specific ubiquitin ligase MuRF1.Circ. Heart Fail. 2019; 12 (30871347)e005234 10.1161/circheartfailure.118.005234Crossref PubMed Scopus (27) Google Scholar, 9Maejima Y. Usui S. Zhai P. Takamura M. Kaneko S. Zablocki D. Yokota M. Isobe M. Sadoshima J. Muscle-specific RING finger 1 negatively regulates pathological cardiac hypertrophy through downregulation of calcineurin A.Circ. Heart Fail. 2014; 7 (24526353): 479-49010.1161/CIRCHEARTFAILURE.113.000713Crossref PubMed Scopus (29) Google Scholar, 10Willis M.S. Rojas M. Li L. Selzman C.H. Tang R.H. Stansfield W.E. Rodriguez J.E. Glass D.J. Patterson C. Muscle ring finger 1 mediates cardiac atrophy in vivo.Am. J. Physiol. Heart Circ. Physiol. 2009; 296 (19168726): H997-H100610.1152/ajpheart.00660.2008Crossref PubMed Scopus (77) Google Scholar, M.S. P. N. H. Glass D.J. Patterson C. cardiac hypertrophy in mice via of 2007; PubMed Scopus Google Scholar, C. H. Patterson C. atrophy cardiac hypertrophy by in an ubiquitin ligase PubMed Scopus Google Scholar). In the study, we that simulated microgravity an in and protein in cultured However, inhibition of calpain the protein of and in cardiomyocytes under microgravity. that calpain mediates NADPH oxidase activation and study demonstrates that inhibition of NADPH oxidase in tail-suspended mouse hearts L. W. L. Li H. L. T. of cardiomyocyte and myocardial in tail-suspended mice by p47phox NADPH oxidase activation and Med. 2019; PubMed Scopus Google the oxidase may a to microgravity-induced myocardial atrophy, which is of and myocardial atrophy myocardial the underlying mechanisms to be that tail suspension for and reduced in mouse However, in heart tail This and may be to a in cardiomyocyte tail suspension in as a cardiomyocyte may a of the of cell Thus, a of is a potential for myocardial induced by microgravity. studies are to the mechanisms by which microgravity myocardial dysfunction. In we an important role of calpain in myocardial abnormalities in tail-suspended mice. Thus, calpain may be a to the heart under conditions of microgravity. that of calpain are under important to future This to the for the and of by the of of mice were the with cardiomyocyte-specific of Capns1 were by mice the and mice with cardiomyocyte-specific of under the of as we Y. J. H. M. D. J.M. T. inhibition of calpain myocardial hypertrophy and in mouse of 1 2011; PubMed Scopus Google Scholar). of Capns1 was by Capns1 in mouse hearts as Y. J. H. M. D. J.M. T. inhibition of calpain myocardial hypertrophy and in mouse of 1 2011; PubMed Scopus Google mice in this study, including were of the was were by the Tail suspension was in mice and their WT to microgravity the L. W. L. Li H. L. T. of cardiomyocyte and myocardial in tail-suspended mice by p47phox NADPH oxidase activation and Med. 2019; PubMed Scopus Google Scholar, unloading Physiol. PubMed Scopus Google Scholar). a of was to the tail and a to a the of to and during the tail or mice were to were with and a to a system with of and the of the were to changes in left ventricular in and and were by under a of Heart were and cardiomyocyte of the heart were and for and with and cardiomyocytes were an analysis system as J. H. L. J.M. T. of NADPH oxidase activation, and myocardial in a mouse of 1 PubMed Scopus Google Scholar). The of cardiomyocytes were in The protein were by Protein was cultured cardiomyocytes a and by a The of in heart was the to the heart were in an The of were with a and 37 The was a in were as Protein was a protein the total of of protein was for in heart was by a the total of of protein was for mice were by cardiomyocytes were and cultured in with and to T. M. via p38 in Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). cardiomyocytes were cultured with size, for we cardiomyocytes on in of with and and through the the ratio of a rotary cell culture system were on their rotary and in a 37 with a and was to L. W. L. Li H. L. T. of cardiomyocyte and myocardial in tail-suspended mice by p47phox NADPH oxidase activation and Med. 2019; PubMed Scopus Google Scholar). were for the with and calpain the or were to culture the time of the rotary The were under simulated microgravity for of protein heart or cell or of protein were the were in for 1 the were with and phosphorylation of Ser-345 and on p47phox and total p47phox p38 and total p38 Cell ERK1/2 and total ERK1/2 Cell and Cell by with The were an of the The protein were for cultured cardiomyocytes and and for heart and was a the was to the of the and as a The of are as and and The were as the ratio of to were in and cell of a as Y. M. T. cardiomyocyte by NADPH calpain Biol. Med. 2009; PubMed Scopus Google Scholar). NADPH oxidase activation was by the of p47phox, and to cell cell were heart a to the The protein of p47phox, and in cell and were and were as for the and oxidase activity was in heart a the total of of protein was for in the were in heart the total of of protein was for in the are as were by by was of was are or with protein left ventricular tail suspension simulated microgravity analysis of

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